Oral quetiapine suspension formulations with extended shelf life and enhanced bioavailability

ABSTRACT

A quetiapine fumarate composition for oral administration is provided comprising a pharmaceutically acceptable salt or solvate of quetiapine existing as a suspension in an aqueous carrier agent. The inventive liquid formulation demonstrates high bioavailability consistent with approved dosage forms, low agglomeration, reduced content of excipients commonly used in solid oral dosage forms and extended shelf life stability. Also provided is a method of manufacturing a liquid quetiapine suspension composition for oral administration and methods of administering therapeutically effective dosages of an oral liquid quetiapine suspension composition to patients in need thereof.

FIELD OF THE INVENTION

The present invention is generally directed to novel suspensionformulations of quetiapine fumarate for therapeutic oral administrationhaving high bioavailability and extended physiochemical stability and toprocesses for preparing and administering such formulations.

BACKGROUND OF THE INVENTION

The invention generally relates to physicochemically stablepharmaceutical formulations for oral administration comprising aneffective amount of quetiapine fumarate in a pharmaceuticallyacceptable, aqueous, suspension-stabilizing vehicle. The activepharmaceutical ingredient (API) quetiapine fumarate 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1)is a well-known compound having anti-psychotic activity first marketedas a tablet under the brand name SEROQUEL™. Quetiapine fumarate has alsobeen referenced as11-[4-[2-(2-hydroxyethoxy)ethyl]Ipiperazinyl]dibenzo[b,f][1,4]thiazepine and Bis[2-[2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl]ethoxy]ethanol](2E)-but-2-enedioate.Further details about this compound are disclosed in the United StatesPharmacopeial Convention Nov. 1, 2015 Revision Bulletin, the disclosureof which is hereby incorporated by way of reference. The preparation,physical properties and pharmacological properties of quetiapinefumarate are further described in published European Patents EP 240,228and 282,236 as well as in U.S. Pat. No. 4,879,288, the entire contentsof which are herein incorporated by reference.

Quetiapine fumarate is able to treat both the positive (hallucinations,delusions) and negative symptoms (emotional withdrawal, apathy) ofpsychosis and is associated with fewer neurological and endocrinerelated side effects compared to older agents. Quetiapine fumarate hasalso been associated with a reduction in hostility and aggression.Quetiapine fumarate is associated with fewer side effects such as EPS,acute dystonia, acute dyskinesia, as well as tardive dyskinesia.Quetiapine fumarate has also helped to, enhance patient compliance withtreatment, ability to function and overall quality of life, whilereducing recidivism (P. Weiden et al., Atypical antipsychotic drugs andlong-term outcome in schizophrenia, 11 J. Clin. Psychiatry, 53-60, 57(1996)). The enhanced tolerability profile of quetiapine is particularlyadvantageous in the treatment of patients hypersensitive to the adverseeffects of antipsychotics (such as elderly patients).

Quetiapine fumarate has plasma half-life of 6 h and poor oralbioavailability due to extensive first-pass metabolism. Quetiapinetablets are available in different API strengths equivalent to 50 mg,100 mg, 150 mg, 200 mg, 300 mg and 400 mg of quetiapine fumarate fororal administration up to twice a day. Other than the present inventiondisclosure, which was fully licensed for use in the UK on Jun. 20 2016,quetiapine fumarate is only marketed as a solid dosage formulationeither under the brand name SEROQUEL™ or various bioequivalent genericsolid dose formulations. Examples of extemporaneously compounded liquidquetiapine fumarate compositions made from solid tablets exist in thecurrent literature, as do various unlicensed formulations in the UK, butthey demonstrate elevated physiochemical instability (e.g., short shelflives, degraded API, agglomeration, etc.) and uncertain bioavailability.

Various pharmaceutical forms are used for oral administration of drugs.In addition to solid single-dose forms such as tablets, hard and softgelatin capsules, liquid forms such as solutions and syrups are alsogiven, in which the dose to be administered can be adjusted by means ofthe volume given.

Individuals often require a high dose of quetiapine for therapeuticeffect. For example a 400 mg tablet, administered twice times a daycontains approximately 800 mg of quetiapine. For certain individuals,quetiapine fumarate can be prescribed at dosages higher than 800 mg/day.When such high doses of quetiapine are combined with excipients, theresulting oral solid dosage form (e.g., tablets) can be prohibitive bothfrom a physical perspective (e.g., difficulty swallowing large tablets)and a chemical perspective (e.g., iatrogenic events resulting fromelevated levels of excipients commonly used in solid oral dosage forms).Moreover, dose titration is difficult with fixed dose formulations. Dosetitration is particularly relevant for neuropsychiatric medicationswhere optimal therapeutic efficacy is often determined on an individualpatient basis. Often, such optimal dosages (e.g., 190 mg) are notavailable in standard solid dose formulations.

Solid dose drug formulations also pose adherence problems. Medicationadherence to solid dose drug formulations is particularly problematic in(i) elderly and pediatric patient populations with swallowingdifficulties, (ii) patients who feign drug ingestion (i.e., “cheeking”)and (iii) patients sensitive to drug excipients normally found in solidoral dose formulations. Solid dose formulations also exhibit a lag timefrom ingestion until therapeutic effects are observed. Liquid oralformulations generally demonstrate faster pharmacodynamics (e.g.,T_(max)) than their solid dose counterpart. This is particularlyimportant for individuals who are either agitated, rapidly escalating oractively experiencing a neuropsychiatric event. Thus, a clear needexists for alternative, non-solid oral formulations of quetiapine withhigh bioavailability and extended physiochemical stability.

Despite a market demand for alternative oral formulations, quetiapinefumarate is marketed only in solid dose formulations (e.g., SEROQUEL™and generic solid dose equivalents). Other than the present invention,there are no known oral liquid quetiapine fumarate formulations approvedas a prescription product. Efforts toward developing shelf-stable, oralliquid formulations of quetiapine fumarate have largely been thwarted bysignificant physiochemical challenges including low API solubility atphysiologic pH and high chemical instability at low pH (i.e., increasingsolubility decreases stability).

Lipid nanoparticle formulations of quetiapine fumarate have beendisclosed, but demonstrate poor bioavailability and significantcommercial manufacturing challenges. U.S. Pat. No. 6,716,416 describesaerosol formulations have been developed for the delivery ofantipsychotics via inhalation, the disclosure of which is herebyincorporated by way of reference. US Pat. App. No. 20050158383 describesthree alternative solid dosage forms of quetiapine hemifurate containinga wax material, press-coat dosage formulations, and controlled releaseformulations, the disclosure of which is hereby incorporated by way ofreference. Shantaram, et. al teaches that hydrogel based nanocrystalformulations of quetiapine fumarate demonstrate moderatebioavailability, but are difficult to manufacture in a consistent andcommercially affordable manner. Extemporaneously prepared quetiapinesuspension formulations originating from compounding pharmaciesgenerally demonstrate no more than thirty-day shelf stability andinconsistent bioavailability. U.S. Pat. No. 6,599,897 teaches away fromstable oral quetiapine liquid suspension formulations and towardsdissolvable quetiapine fumarate granules lacking suspending agents suchas xanthan gum, the disclosure of which is hereby incorporated by way ofreference.

The present invention generally describes novel oral liquid suspensionquetiapine fumarate compositions of varying API concentrations havingcommercially relevant physiochemical stability and bioavailabilitygenerally bioequivalent to that of currently marketed solid doseformulations. An exhaustive written description of the disclosedinvention is described at the Public Assessment Report (PAR) forQuetiapine Rosemont 20 mg/ml Oral Suspension (PL 00427/0240;UK/H/5869/001/DC), the entire contents of which are herein incorporatedby reference. The present invention is the first and only known oralliquid formulation of quetiapine fumarate that has received regulatoryapproval as a prescription drug product.

For certain patient populations, the disclosed oral liquid formulationsare a discernible improvement over (i) previously disclosed andcommercially marketed solid oral dosage forms of quetiapine fumarate(i.e., SEROQUEL™), (ii) generic equivalent solid dosage formulations aswell as (iii) extemporaneously compounded liquid formulations. Thepresent invention also generally discloses methods of preparing suchoral liquid quetiapine formulations as well as methods of treatment withoral liquid quetiapine formulations.

SUMMARY OF THE INVENTION

The present invention relates generally to physicochemical stableaqueous compositions comprising a pharmaceutically effective amount ofquetiapine fumarate, pharmaceutically acceptable vehicle and athickening agent in suspension. The present compositions containquetiapine fumarate between about 2 mg/mL to about 40 mg/mL ofquetiapine fumarate. More preferably the concentrations of quetiapinefumarate are about 12.5 mg/5 ml, 25 mg/5 ml, 100 mg/5 ml and 200 mg/5 ml(i.e., 2.5 mg/ml, 5 mg/ml, 20 mg/ml and 40 mg/ml, respectively). Themost preferred compositions of the present invention containapproximately 20 mg/ml to 40 mg/ml quetiapine fumarate that remainsphysicochemically stable for at least twenty-four months. It will beapparent to those skilled in the art that such formulations can beco-administered with other therapeutic or prophylactic agents and/ormedicaments that are not medically incompatible therewith.

The inventive oral composition has quetiapine fumarate in a suspensionformulation and can optionally include, for example, at least onepharmaceutical excipient selected from a buffer, an antioxidant, achelating agent, a preservative, a tonicity adjuster, a cyclodextrin, asurfactant, a suspending agent, a wetting agent, a stabilizer, aflocculating agent, a sweetener, a flavoring, a colorant, a cosolvent,and other ingredients. Oral liquid formulations can containtaste-masking ingredients such as sweeteners (artificial and/or natural)and flavorings.

The manufacture of the API used in the inventive composition isdescribed in FIG. 1. The method summarizes the reaction of11-piperazin-1-yldibenzo[b,f][1,4]thiazepine dihydrochloride with2-(2-chloroethoxy) ethanol in toluene and N-methylpyrrolidone assolvents, at reflux temperature in the presence of a strong base (toafford the free base of the dibenzo derivative prior to the reaction)and sodium iodide (to obtain 2-(2-iodooethoxy) ethanol prior to thereaction, which is more reactive than the chloro derivative). Once thereaction is over, the quetiapine base obtained is reacted with fumaricacid to obtain the desired fumarate salt.

The inventive compositions generally have a pH of between about 5.0 toabout 6.0 and are comprised according to FIG. 2. A preferred embodimenthas a pH of between about 5.2 to about 5.8. The inventive compositionsare manufactured according to FIG. 3 and the following:

-   -   Add Purified Water (A) to the main vessel.    -   Add the Citric Acid Monohydrate to the main vessel and mix until        dissolved using a high-shear mixer.    -   Add the Disodium Hydrogen Phosphate Dihydrate to the main vessel        and mix until dissolved using a high-shear mixer.    -   Add Sucralose to the main vessel and mix until dissolved using a        high-shear mixer.    -   Add the Simethicone Emulsion (Q7-2587 30%) to the main vessel        and mix until dispersed using a high-shear mixer.    -   Add Quetiapine Fumarate to the main vessel and mix using a        high-shear mixer until a homogeneous suspension is produced.    -   To a separate stage vessel add the Propylene Glycol.    -   To the separate stage vessel add Methyl Hydroxybenzoate    -   To the separate stage vessel add Propyl Hydroxybenzoate and mix        using a high-shear mixer until dissolved.    -   To the preservative solution in the separate stage vessel add        Xanthan Gum and mix until homogenous using a propeller mixer.    -   Add the preservative solution/Xanthan Gum slurry in the separate        stage vessel to the main vessel and mix using a high-shear mixer        until a uniformly thickened suspension is produced.    -   Add the Lemon Flavour to the main vessel and mix with a        high-shear mixer until dispersed.    -   Check the pH of the solution (target pH is 5.50). If the pH is        outside the range of 5.2-5.8 adjust the pH until it within this        range by using either 10% w/v Citric Acid Monohydrate solution        to lower pH or a 10% w/v Disodium Hydrogen Phosphate Dihydrate        solution to increase the pH.    -   Add Purified Water (B) to make to final volume and mix until        dispersed using a high-shear mixer.    -   Fill 152±2 ml of finished product into 180 ml amber glass        bottles and close with child resistant closures.

The basic principle of manufacture of the bulk drug suspension productis the use of stainless steel mixers in stainless steel 316pharmaceutical grade vessels to suspend ingredients in suspending agentsuntil a homogeneous suspension is obtained. The following is a list ofessential equipment: 100 L Stainless steel tank; Medium high shear mixer(50 L-200 L); Bench top high shear mixer (<10 L); Bench top air drivenpropeller mixer (<10 L); Mobile electric propeller mixer (SOL-400 L).Critical intermediates of the inventive composition can be monitored andcontrolled according to the in-process control limits described in FIG.4.

The inventive formulation may be used to treat a patient in need of aneffective amount of quetiapine fumarate. The present invention furtherprovides methods of treating at least one symptom or conditionassociated with but not limited to:

-   -   1) Schizophrenia and other Psychotic Disorders including but not        limited to Psychotic Disorder, Schizophreniform Disorder,        Schizoaffective Disorder, Delusional Disorder, Brief Psychotic        Disorder, Shared Psychotic Disorder, and Psychotic Disorder Due        to a General Medical Condition;    -   2) Dementia and other Cognitive Disorders;    -   3) Anxiety Disorders including but not limited to Panic Disorder        Without Agoraphobia, Panic Disorder With Agoraphobia,        Agoraphobia Without History of Panic Disorder, Specific Phobia,        Social Phobia, Obsessive-Compulsive Disorder, Post Traumatic        Stress Disorder, Acute Stress Disorder, Generalized Anxiety        Disorder and Generalized Anxiety Disorder Due to a General        Medical Condition;    -   4) Mood Disorders including but not limited to a) Depressive        Disorders, including but not limited to Major Depressive        Disorder and Dysthymic Disorder and b) Bipolar Depression and/or        Bipolar mania including but not limited to Bipolar I Disorder,        including but not limited to those with manic, depressive or        mixed episodes, and Bipolar n Disorder, c) Cyclothymic        Disorder, d) Mood Disorder Due to a General Medical Condition;    -   5) Sleep Disorders;    -   6) Disorders Usually First Diagnosed in Infancy, Childhood, or        Adolescence including but not limited to Mental Retardation,        Learning Disorders, Motor Skills Disorder, Communication        Disorders, Pervasive Developmental Disorders, Attention-Deficit        and Disruptive Behavior Disorders, Feeding and Eating Disorders        of Infancy or Early Childhood, Tic Disorders, and Elimination        Disorders;    -   7) Substance-Related Disorders including but not limited to        Substance Dependence, Substance Abuse, Substance Intoxication,        Substance Withdrawal, Alcohol-Related Disorders, Amphetamine (or        Amphetamine-Like)-Related Disorders, Caffeine-Related Disorders,        Cannabis-Related Disorders, Cocaine-Related Disorders,        Hallucinogen-Related Disorders, Inhalant-Related Disorders,        Nicotine-Related Disorders, Opioid-Related Disorders,        Phencyclidine (or Phencyclidine-Like)-Related Disorders, and        Sedative-, Hypnotic- or Anxiolytic-Related Disorders;    -   8) Attention-Deficit and Disruptive Behavior Disorders;    -   9) Eating Disorders;    -   10) Personality Disorders including but not limited to        Obsessive-Compulsive Personality Disorder; and    -   11) Impulse-Control Disorders, comprising administering to a        mammal a therapeutically effective amount of a formulation of        the invention.

Other medical indications known to be responsive to quetiapine fumaratetreatment are within the scope of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the API manufacturing process.

FIG. 2 shows the excipient concentrations (% w/v) for finished productstrengths of quetiapine fumarate.

FIG. 3 shows the manufacturing process of quetiapine fumarate oralsuspension.

FIG. 4 shows the control of critical steps and intermediates.

FIG. 5 shows the solubility chart for quetiapine fumarate.

FIG. 6 shows API Stability. 10 mg/mL solutions of each batch ofQuetiapine Fumarate were prepared in 65:35 acetonitrile:water diluent. 5mL of each of these solutions were degraded according to the followingconditions: Control (non-degraded sample solution); Heat (Refluxed for 2hours with 5 mL of purified water); Metal (Refluxed for 2 hours with 5mL of a solution containing 10 ppm Fe ions); Base (Refluxed for 2 hourswith 5 mL of 1M sodium hydroxide); Acid (Refluxed for 2 hours with 5 mLof 1M hydrochloric acid); Peroxide (Refluxed for 2 hours with 5 mL of0.5 vol hydrogen peroxide). Following reflux, the samples were cooled,transferred to volumetric flasks and diluted to 50 mL with 65:35acetonitrile:water diluent.

FIG. 7 shows the API starting particle diameter, dissolution recovery,and agglomeration.

FIG. 8 shows finished product prepared with API of varied particle size.

FIG. 9A shows dissolution of 100 mg/5 mL samples prepared with variedparticle size drug substance (pH6.8 media).

FIG. 9B shows the effect of particle size on dissolution rate inquetiapine oral suspensions.

FIG. 10 shows quetiapine batch dissolution profiles.

FIG. 11 shows quetiapine fumarate polymorphic forms.

FIG. 12 shows XRPD Analysis of starting API.

FIG. 13 shows representative XRPD analysis of liquid quetiapinesuspensions.

FIG. 14 shows XRPD peaks of quetiapine fumarate: API and suspensionsversus literature values.

FIG. 15 shows finished product maximum daily excipient levels.

FIG. 16A shows particle size and viscosity data for production scalebatches.

FIG. 16B shows particle size for additional production scale batches.

FIG. 16C shows viscosity data for additional production scale batches.

FIG. 17 shows 90% confidence intervals for quetiapine meantest/reference ratios.

FIG. 18 shows pharmacokinetic parameters of oral quetiapine fumaratesuspension vs. tablet.

DETAILED DESCRIPTION OF THE INVENTION

To date, the only U.S. approved formulations of quetiapine fumarate aresolid dosages (e.g., SEROQUEL™ and their generic equivalents). Forexample, U.S. Pat. No. 7,959,948 describes a solid dosage extendedrelease quetiapine fumarate pharmaceutical composition comprising (i)quetiapine or a pharmaceutically acceptable salt thereof (ii) a mixedexcipient comprising an intimate admixture of polyvinylacetate andpolyvinylpyrrolidone in a weight ratio from 5:2 to 10:2; and, optionally(iii) an acid, especially fumaric acid. U.S. Pat. No. 6,214,286describes prompt-release oral pharmaceutical compositions for thecreation of “ready-to-use” extemporaneous suspensions where the activeagent is in microgranule form coated with a lipid film coating mixture.U.S. Pat. No. 7,794,750 describes solid dose, controlled-releaseformulations of quetiapine. U.S. Pat. App. No. 2007/0031340 describes anaerosol producing drug delivery device and thin-film formulation ofquetiapine. U.S. Pat. No. 5,156,842 describes a non-aqueouspharmaceutical liquid suspension for oral administration comprising anAPI suspended in an edible, non-aqueous carrier vehicle (e.g., mineraloil) in the form of controlled release particles. U.S. Pat. No.6,599,897 discloses dissolvable quetiapine fumarate granules lackingsuspending agents. The entire contents of the above U.S. patent andpatent applications are herein incorporated by reference.

Medication compliance is an essential component of successful treatmentfor neuropsychiatric disorders. Medication adherence to solid dose drugformulations is particularly problematic in (i) elderly and pediatricpatient populations with swallowing difficulties, (ii) patients whofeign drug ingestion (i.e., “cheeking”) and (iii) patients who aresensitive to drug excipients normally found in solid dose formulations.

Possible solutions for enhancing solid dose medication compliance wouldbe the development of physicochemically stable bioequivalent oral liquidformulations (e.g., solutions, emulsions, suspensions, and syrups withlong shelf lives). Relative to solid dose formulations, oral liquidformulations are easier to swallow, demonstrate faster absorptionkinetics, and are easier to titrate on a per patient basis. Otherpossible solutions could include the development of easier to swallowtablets, capsules, sustained release formulations, transdermal patches,suppositories, lozenges, parenteral formulations, ocular formulations,inhalation formulations, sublingual tablets, topical formulations (e.g.,creams, ointments, gels, pastes, lotions, powders), and/or easilyreconstituted lyophilized formulations.

For patients who have difficulty in swallowing, feign ingestion, arechildren or are seeking alternatives to oral solid dosage forms,pharmacies are often forced to individually compound liquid formulationsusing crushed quetiapine. Such extemporaneously created suspensions ofquetiapine fumarate are problematic in part because they are notphysicochemically stable (e.g., over time the active agent settles outof the compounded formulation or is degraded) leading to highly variableAPI dosing with accompanying unpredictable therapeutic efficacy. Thefailure of others to develop a liquid oral quetiapine formulation,despite a commercial demand, suggests that while those of ordinary skillin the art may have already attempted to develop such oral liquid drugsuspensions, extensive physiochemical barriers preclude a reasonableexpectation of success. Indeed, U.S. Pat. No. 8,057,811 highlights thedifficulties of formulating aqueous suspensions of a relatedanti-psychotic, clozapine, and is hereby incorporated by reference.

A buffer or buffer system can be optionally added to the liquid, forexample, to maintain pH in a desired range, retain antimicrobialactivity or enhance the solubility of the pharmaceutically active agent.Suitable buffers are those that are not chemically reactive with otheringredients and are present in amounts sufficient to provide the desireddegree of pH buffering. In some embodiments, the buffer is selected toassist in maintaining a slightly acidic pH of the liquid formulation andto balance electrical charges among API, suspending agents, andexcipients allowing for optimal drug performance characteristics. In apreferred embodiment, the buffer is a buffer system comprising a bufferpair of citric acid monohydrate and di-sodium hydrogen phosphatedihydrate.

Quetiapine fumarate is a weak acid with dissociation constant (pKa) 3.3and 6.8 with moderate pH dependent solubility, 94.3 mg/ml to 2.37 mg/mlat pH values from 1 to 9 reported. At lower pH, where quetiapine is verysoluble (1.499 g/5 ml at pH2 and 952.1 mg/5 ml at pH3), acidic solutionstend to promote API degradation as well as impart undesirable acidictaste. As pH increases, the solubility of quetiapine fumarate rapidlydecreases FIG. 5. This application discloses the first example of anaqueous suspension of quetiapine fumarate with extended physicochemicalstability and therapeutic bioavailability equivalent to that ofcommercially approved solid dose formulations.

Liquid oral drug suspension formulations are far more complex andunpredictable than their fully soluble liquid formulation counterparts.For drugs with low solubility and/or bioavailability at physiologicalpH, efforts to develop suspension formulations are often met withvarying rates of success due to restrictive physiochemical parameters ofthe API and/or excipients. While simply increasing the volume of diluentfor low-solubility drugs may lead to improved solubility, the largevolume of diluent is often prohibitive from a patient perspective.Formulations in which the drug is solubilized using a co-solvent(s)often demonstrate unforeseeable precipitation and/or phase separationduring long-term storage. Finally, as is the case for quetiapinefumarate, forcing an API into solution often requires conditions (e.g.,pH <3.5) well out of the range of acceptable oral tolerability.

Therapeutically effective quetiapine suspensions are particularlyproblematic since the API and subsequent oral suspension formulationsmust not only exhibit high bioavailability, but also highphysicochemical stability. FIG. 6 discloses the chemical stability offour commercial lots of the API. While we hypothesized that APIdegradants or impurities could contribute to formulation difficulties,we observed no substantive differences among all API sources.

The necessity for drug products to have extended shelf lives (e.g.,longer than 12 months) is highlighted by the retail pharmacy practice ofroutinely returning drug products (including neuropsychiatric drugs)with remaining shelf lives of less than twelve months. While drugs insuspensions are generally chemically more stable than in fully solublesolutions, the chemical stability often comes at the expense ofunpredictable physical instability—drug suspensions tend to settle,phase separate, marble and/or agglomerate upon storage leading tounacceptably high variations in dosing. FIG. 7 describes the APIstarting particle diameter, dissolution recoveries, and agglomeration ofeight different development batches of product using API provided byfour different source manufacturers.

The size and relative distribution of particle sizes of the drugsubstance was recognized as a critical component during the developmentprocess. A preferred embodiment of the invention will include quetiapinefumarate with a relative particle size distribution D (v, 0.9) between30 μm and 60 μm. FIG. 8 describes 100 mg/5 ml suspensions produced withAPI of various particle sizes during the development process. FIG. 9aand FIG. 9b describe the dissolution profiles of the 100 mg/5 mlsuspensions at pH 6.8.

Highlighting the unpredictability of developing a liquid suspension ofquetiapine fumarate capable of retaining physicochemical stability, onlyone of four formulation concentrations (i.e., 20 mg/ml) had sufficientphysicochemical shelf stability (i.e., 24 months), acceptablebioavailability (i.e., equivalent to the approved solid dose SEROQUEL™formulation) and contained levels of excipients that were deemed safefor human exposure such that it could receive regulatory marketingapproval (See MHRA, Procedure No: UK/H/5869/001/DC and UK License No: PL00427/0240).

The rate of sedimentation of a suspended phase can be estimated byStoke's equation (i.e., V=d² (ρ1−ρ2)g/18 ηo). While a useful startingpoint, this equation assumes that (i) all dispersed particles are ofuniform shape and size and (ii) that the particles are sufficiently farapart so that the movement of one does not affect the neighboringparticles. Moreover, the Stokes' equation does not consider all theadditional variables affecting the stability of a suspension, includingbut not limited to, particle size and purity of both API and excipients,storage temperature, electrical charge of API and excipients,concentration of suspending agent, use of surfactants and wettingagents, antifoaming agents, co-solvents, pH adjusting buffer systems,antimicrobial preservatives and physiochemical compatibility withpackaging materials (e.g., plastics, glass, rubber).

While drug suspensions can facilitate chemical stability, drugsuspensions often exhibit detrimental physical instability due, in part,to unpredictable particle-particle interactions (e.g., caking and/orcompaction of API and/or excipients) as well as complex particle-aqueoussolution interactions. Settling and aggregation often result in drugformulations that are difficult to resuspend and/or are susceptible tophase separation leading to variable dose administration.

Ideal drug suspension formulations are pseudoplastic—demonstrating highviscosity at low shear rates (e.g., during shelf storage) and lowviscosity at high shear rates (e.g., during shaking and pouring).Pseudoplastic suspending agents (as well as thixotropic agents) aredesirable, since they recover slowly from the deformation that occursthrough shearing (i.e., upon shaking, they remain fluid long enough tobe poured). We observe pseudoplasticity in the 20 mg/ml quetiapinefumarate formulation. Preferred compositions will retain a viscosityrange of between 700-2000 cP at 25 degrees centigrade over the shelflife of the product.

While controlled flocculation has been shown to prevent caking (SuckerH., Fuchs P., Speiser P., Pharmazeutische Technologie, 5th Edition 1991,Georg Thieme Verlag, Stuttgart, p. 423), the commercial manufacture ofstable suspensions by controlled flocculation is subject to limitations,since it is difficult to reproduce the optimum properties of suspensionsystems owing to the variability of the suspended solid and thestability of the excipients.

Another potential source of physiochemical instability in suspensiondrug formulations lies in the source manufacturer of the API. Forunknown reasons, batches of quetiapine fumarate produced with comparablelaboratory specifications (e.g., USP grade drug substance with varyingparticle size controls) demonstrated surprisingly disparatephysiochemical behavior when in suspension (compare FIG. 7, columns 2, 4and FIG. 10). For clarity, FIG. 7 shows that suspensions produced withdrug substance from manufacturers B and D show significant agglomerationin suspension at release, whereas suspensions produced with drugsubstance from manufacturers A and C do not. FIG. 10 highlights thevariability in batch dissolution profiles of final oral suspensionproduct made from various API sources.

The consistency of the physiochemical characteristics of the disclosedoral suspensions are typically influenced by a large number ofvariables, for example; the density of the internal and external phases;the ratio of the phase volumes; the viscosity of the external phase; andthe dimensions, degree of aggregation, and shape of the particles. Thevariability of these parameters can cause difficulties during thedevelopment of the suspension, even after agitation at the time of use.In some cases, the difficulties lead to a nonhomogeneous distribution ofthe active agent.

Agglomeration is often an unpredictable physiochemical problem whendeveloping drug suspension products. Agglomeration can modify themicrometric properties of pharmaceutical powders (e.g., flowability,packability and solubility) in unforeseen ways. Agglomeration can alsoinfluence phase segregation during processing and affect productbioavailability. Yari, et al. describes difficulties in understandingand reproducibly controlling process parameters governing agglomeration,the entire contents of which are herein incorporated by reference. Inparticular, Yari describes the uncertainties of how agglomerates formand evolve during the drug suspension manufacturing process usingcarbamazepine as a model API. Results show that agitation can influencethe shape of the agglomerated particles in an unpredictable manner andthat agglomeration of large crystals is often more difficult if they areelongated in shape. Smaller crystals on the other hand give rise to morespherical and larger agglomerates with smoother surface and denserstructure.

Since there is no information in the art that would explain thedifference in performance of comparable quetiapine fumarate API, andwithout being bound to any particular theory, we propose that an as yetuncharacterized physiochemical property related to the starting material(e.g., particle size, particle shape and/or trace polymorphisms)contributed, at least in part, to the inability of others tosuccessfully develop a commercially viable, physicochemically stableliquid oral quetiapine formulation. Mentioned earlier, the presentinvention is the first and only known example of a liquid oralquetiapine product that has received regulatory approval for use as alicensed prescription product.

If necessary, the physical stability of drug suspensions can becontrolled by the addition of flocculating agents to enhance particledispersion and/or the addition of viscosity enhancers to reducesedimentation rate in the flocculated suspension. While viscosityenhancers typically range from 0.5% to 5% of the final formulation, theideal viscosity largely depends on a particle's unique chemistry andtendency to settle. Non-limiting examples of flocculating agentsinclude, but are not limited to, electrolytes (e.g., KCL, NaCl),sulfates, citrates, phosphate salts, pH adjusting agents, alum,aluminium chlorohydrate, aluminium sulfate, calcium oxide, calciumhydroxide, iron (II) sulfate (ferrous sulfate), iron (III) chloride(ferric chloride), polyacrylamide, polyDADMAC, sodium aluminate, sodiumsilicate, chitosan, isinglass, moringa oleifera seeds, gelatin,strychnos potatorum seeds, guar gum, and alginates.

A suspension system was next explored as a means to limit physicalinstability of the inventive composition while maintaining highbioavailability. Exemplary suspending agents include: acacia,tragacanth, xanthan gum, carbomer, alginates, carrageenan, locust beangum, guar gum, gelatin, methylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, microcrystalline cellulose, powderedcellulose, hydroxy ethylcellulose, sodium carboxymethylcellulose (CMC),and synthetic hydrocolloids such as Carbopol™. Bentonite, Hectorite,attapulgite, and Veegum K have also been used as suspending agents withmixed success.

After several suspending agents, and combinations thereof, were shown toadsorb quetiapine fumarate, it was determined that xantham gum by itselfcould be a viable suspending agent. While xantham gum demonstrated >99%recovery, after 2 weeks storage, the 20 mg/ml product began to settleand phase separate. Increasing xantham gum concentration up to andincluding 50% failed to correct the physiochemical instability of the 20mg/ml product. Surprisingly, when the concentration of the citrate:phosphate buffer was doubled the inventive product became fullystabilized. In an embodiment, 0.4% w/v xantham gum was adequate tosuspend quetiapine fumarate fumarate for an extended shelf stability atAPI loadings from 12.5 mg/5 ml to 200 mg/5 ml with citrate phosphateranges from 0.9-1.8% w/v and disodium hydrogen phosphate ranges from2.0-4.0% w/v

Another potential source of unpredictability in suspension drugformulation development lies in the existence of chemical polymorphism.Many pharmaceutical compounds can crystallize with more than one type ofmolecular packing structure and/or with more than one type of internalcrystal lattice. This phenomenon of identical chemical structure butdifferent internal structure is generally referred to as polymorphism.Species having different molecular structures are referred to aspolymorphs. Many pharmacologically active organic compounds can alsocrystallize such that a second, foreign molecule(s), especially solventmolecules, are regularly incorporated into the crystal structure of theprincipal pharmacologically active compound. This phenomenon is referredto as pseudopolymorphism and the resulting structures aspseudopolymorphs. When the second molecule is a solvent molecule, thepseudopolymorphs can be referred to as solvates. An importantsolid-state property of a pharmaceutical compound that can vary amongpolymorphs is its rate of dissolution in aqueous media (e.g., gastricfluid) and thus bioavailability. For a general review of polymorphs andthe pharmaceutical applications of polymorphs see G. M. Wall, PharmManuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58,911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), whichis incorporated herein by reference.

Quetiapine fumarate is known to exhibit polymorphism (FIG. 11). Weinvestigated if polymorphism could be responsible for the failure ofothers to develop an oral liquid suspension of quetiapine fumarate.Powder X-Ray diffraction was carried out on a Bruker-AXS D8 Advance XRPDmachine using 9 mm & 25 mm cavity PMMA sample holders. Manufacturer'sAPI was loaded into 25 mm sample reception PMMA holder and analyzed from2-40° 2theta (0.04° 2theta step size and 0.2 second dwell time—Agenda1“Routine” conditions, Slits V20, using the LynxEye™ detector).Polymorphic analysis of all API manufacturing sources suggested thatquetiapine fumarate to be generally of Form 1 (FIG. 12). Subsequent XRPDanalysis of the inventive oral formulations similarly identifiedquetiapine fumarate in suspension as Form 1 suggesting that polymorphismdid not change once API was suspended as an aqueous formulation (FIG.13.)

All of the XRPD peaks present in the inventive formulations wereattributable to API. No other API polymorphs were detected and noformulation excipients were seen in crystalline form. Diffractionpatterns of the four suspension formulations (12.5 mg/5 ml, 25 mg/5 ml,100 mg/5 ml, 200 mg/5 ml) of different time points were seen to beessentially identical, strongly suggesting that the API component is notchanging polymorphic form during shelf storage. It is worth noting thatthe XRPD pattern for quetiapine fumarate is quite complex. Only thestrongest peaks were characterized (>30% intensity). Not wishing to bebound by theory, it is possible that other polymorph contaminants existmay contribute to the physiochemical stability and/or bioavailability ofthe disclosed invention. The XRPD pattern observed for the starting APIis significantly sharper than those obtained for the oral suspensions,the latter demonstrating a more amorphous pattern. As such, the peakpositions for the oral suspensions may not be as precise as those forthe starting API.

The manufacturing process for the quetiapine fumarate suspension drugproduct required use of a high shear mixer to hydrate the suspendingagent and ensure efficient dispersion of the active. This in turnaerates the product and produces excessive foam on the surface of theproduct. It was determined that the use of an antifoaming agent waslikely necessary. A variety of antifoaming agents exist, including: oilbased defoamers (e.g., ethylene bis stearamide (EBS), paraffin waxes,ester waxes and fatty alcohol waxes), powder defoamers (e.g., silica),water based defoamers (e.g., mineral oil, vegetable oil, long chainfatty alcohol, fatty acid soaps or esters), silicone based defoamers(e.g., Polydimethylsiloxane), EO/PO based defoamers (e.g., polyethyleneglycol and polypropylene glycol copolymers) and alkyl polyacrylates.Simethicone emulsion was ultimately found to be compatible with the API(and excipients) and able to ensure a suspension product that did notseparate for at least a twenty-four month shelf life.

It is preferable that solid API particles distribute homogeneously inthe suspension to ensure accurate and reproducible dosing.Unfortunately, solid particles of suspension are not easily wetted bywater due to their hydrophobic nature. Some wetting agent, acting assurfactants, accomplish this by reducing the interfacial tension betweenthe solid particle and the liquid medium. Surfactants have disadvantagesin that (i) they have foaming tendencies, (ii) are bitter in taste, and(ii) interact with preservatives (e.g., methyl paraben) and reduceantimicrobial activity. Surfactants can generally include: polymericsurfactants, anionic surfactants cationic surfactants, non-ionicsurfactants and amphoteric surfactants. Non-limiting specific examplescan include sodium lauryl sulfate, glyceryl laurate, polyoxamers andbenzalkonium chloride. Surprisingly, the disclosed invention did notrequire surfactants to ensure uniform particle distribution andconsistent API dosing.

Pharmaceutical excipients are pharmaceutically acceptable ingredientsthat are essential constituents of virtually all pharmaceuticalproducts. The inventive pharmaceutical suspensions may comprise at leastone additional component selected from the group consisting ofexcipients, surface active agents, dispersing agents, sweetening agents,flavoring agents, coloring agents, preservatives, oily vehicles,solvents, suspending agents, dispersing agents, wetting agents,emulsifying agents, demulcents, buffers, salts, spreading agents,antioxidants, antibiotics, antifungal agents and stabilizing agents.

While drug excipients often improves physiochemical stability in soliddosage formulations, the presence of excipients in suspensionformulations is another source of both chemical and physical variabilitythat can impact influence final product. Moreover, many excipients areknown to be toxic above certain individual thresholds or in combinationwith other excipients and/or APIs. Persons of ordinary skill in the artwould understand that both the U.S. Food and Drug Administration (FDA),the World Health Organization (WHO) and other related entities listmaximum recommended daily intake limits of drug excipients to avoidexcipient mediated toxicities. The World Health Organization (WHO) hasspecified a maximum daily allowance limit for the following excipientspresent within the inventive formulation FIG. 15.

Non-limiting examples of excipients individually suspected of causingadverse events include: acacia, acesulfame, acesulfame potassium, aceticacid, acetone, acetyltributyl citrate, alcohol, alginic acid,alpha-tocopherol, aluminum chloride, aluminum chlorohydrex propyleneglycol, aluminum hydroxide, aluminum lake dyes, aluminum oxide, aluminumsilicate, aluminum stearate, aluminum sulfate, amide resin,aminobenzoate sodium, ammonia ammonio methacrylate copolymer, ammoniomethacrylate copolymer type A, ammonio methacrylate copolymer type B,ammonio methacrylate copolymers, ammonium chloride, ammonium hydroxide,ammonium laureth-5 sulfate, ammonium phosphate dibasic, artificialflavor, artificial grape flavor, artificial mint flavor, ascorbic acid,ascorbyl palmitate, aspartame, aspartame powder, banana barium sulfate,benzalkonium chloride, benzoic acid, benzyl alcohol, betadex blackcurrant, black currant flavor, black ink black pigment, blackberry, bluedye, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluenebutylparaben, calcium, calcium carbonate, calcium phosphate, calciumphosphate dibasic anhydrous, calcium phosphate dihydrate dibasic,calcium silicate, calcium stearate, calcium sulfate, calcium sulfateanhydrous, calcium sulfate dehydrate, candelilla wax, candelilla waxpowder, carbomer, carbomer 934, carbomer 934p, carbomer homopolymer typeA, carbomer homopolymer type B, carbomer homopolymer type C,carboxymethylcellulose, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carmine, carnauba wax, carrageenan,castor oil, castor wax, cellacefate, cellulose, cellulose acetate,cellulose compounds, cellulose powdered, cellulosic polymers,cetostearyl alcohol, cetyl alcohol, cetylpyridinium chloride, cherry,citric acid, citric acid anhydrous, citric acid monohydrate, cochineal,coconut oil colophony colorants, coloring agent, compressible sucrose,compressible sugar, confectioners sugar, copovidone, corn, corn oil,corn starch, corn syrup, corn syrup solids, corn-derived proteins,cottonseed oil, cranberry, croscarmellose sodium, croscarmellose sodiumtype A, crospovidone, cysteine hydrochloride, D&C Blue No. 1, D&C GreenNo. 5, D&C Red No. 21, D&C Red No. 22, D&C Red No. 27, D&C Red No. 27Aluminum Lake, D&C Red No. 27 Lake, D&C Red No. 28, D&C Red No. 28Aluminum Lake, D&C Red No. 30, D&C Red No. 30 Aluminum Lake, D&C Red No.33, D&C Red No. 40, D&C Red No. 6, D&C Red No. 6 Lake, D&C Red No. 7,D&C Red No. 7 Calcium Lake, D&C Yellow No. 10, D&C Yellow No. 10Aluminium Lake, D&C Yellow No. 10 Lake, D&C Yellow No. 5, D&C Yellow No.6, dehydrated alcohol, dextrates, dextrose, dextrose monohydrate,dibasic calcium phosphate, dibutyl phthalate, dibutyl sebacate,dicalcium phosphate, diethyl phthalate, dihydroxyaluminum sodiumcarbonate, dimethicone, dimethylaminoethyl methacrylate-butylmethacrylate-methyl methacrylate copolymer, dimethylpolysiloxanedocusate sodium, dyes, edetate calcium disodium, edetate disodium edibleblack ink, egg lecithin, erythrosine, erythrosine sodium, ethanolamine,ethyl acrylate-methyl methacrylate copolymer, ethyl alcohol, ethylbutyrate, ethyl isovalerate, ethylcellulose ethylcellulose (10 mPa·s),ethylcellulose (100 mPa·s), ethylcellulose (20 mPa·s), ethylcellulose (7mPa·s), ethylcelluloses, ethylene glycol monoethyl ether, ethylvanillin,eudragit FD&C Blue No. 1, FD&C Blue No. 1 Aluminium Lake, FD&C Blue No.1 Lake, FD&C Blue No. 2, FD&C Blue No. 2 Aluminium Lake, FD&C Blue No. 2Lake, FD&C Green No. 3, FD&C Green No. 3 Aluminum Lake, FD&C Red No. 3,FD&C Red No. 4, FD&C Red No. 40, FD&C Red No. 40 Aluminium Lake, FD&CRed No. 40 Lake, FD&C Yellow No. 10, FD&C Yellow No. 10 Aluminum Lake,FD&C Yellow No. 10 Lake, FD&C Yellow No. 5, FD&C Yellow No. 5 AluminumLake, FD&C Yellow No. 5 Lake, FD&C Yellow No. 6, FD&C Yellow No. 6Aluminum Lake, FD&C Yellow No. 6 Lake, ferric oxide, ferric oxide black,ferric oxide brown, ferric oxide orange, ferric oxide red, ferric oxideyellow, ferric oxides, ferrosoferric oxide, ferrous fumarate, ferrousoxide, flavor, flavors, fragrances, fumaric acid, gelatin, glucosamine,glucosamine hydrochloride, glutamic acid hydrochloride, glycerin,glycerol, glycerol monooleate, glycerol monostearate, glyceryl behenate,glyceryl distearate, glyceryl monooleate, glyceryl monostearate,glyceryl triacetate, glycine, glycolate, glycyrrhizin ammoniated, guargum, hard gelatin capsule, hard paraffin, hydrochloric acid,hydrochloric acid, hydrogen peroxide, hydrogenated castor oil,hydrogenated cottonseed oil, hydrogenated soy oil, hydrogenated soybeanoil, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, hypromellose, hypromellose 2208, hypromellose 2208 (100mPa·s), hypromellose 2208 (100000 mPa·s), hypromellose 2208 (15000mPa·s), hypromellose 2208 (3 mPa·s), hypromellose 2208 (4000 mPa·s),hypromellose 2910, hypromellose 2910 (15 mPa·s), hypromellose 2910(15000 mPa·s), hypromellose 2910 (3 mPa·s), hypromellose 2910 (5 mPa·s),hypromellose 2910 (50 mPa·s), hypromellose 2910 (6 mPa·s), hypromellose2910 3 cp, hypromellose 2910 50 cp, hypromellose 2910 5 cp, hypromellose2910 6 cp, hypromellose 3 cp, hypromellose 5 cp, hypromellose 6 cp,hypromellose phthalate, hypromelloses, indigotindisulfonate sodium,iron, isobutylparaben, isopropyl, isopropyl alcohol, lactitol, lactitolmonohydrate, lactose, lactose anhydrous, lactose hydrous, lactosemonohydrate, lecithin, lemon oil, leucine, light mineral oil, lowsubstituted hydroxypropyl cellulose, magnesium, magnesium aluminumsilicate, magnesium carbonate, magnesium hydroxide, magnesium oxide,magnesium oxide heavy, magnesium silicate, magnesium stearate, magnesiumtrisilicate, maleic acid, malic acid, maltodextrin, mannitol,medium-chain triglycerides, meglumine, menthol, methacrylic acid,methacrylic acid-ethyl acrylate copolymer (1:1) type a, methacrylicacid-methyl methacrylate copolymer (1:1), methacrylic acid-methylmethacrylate copolymer (1:2), methacrylic acid copolymer, methacrylicacid copolymer type B, methanol, methyl alcohol, methyl cinnamate,methyl methacrylate, methylcellulose, methylcellulose (100 mPa·s),methylcellulose (15 mPa·s), methylcellulose (400 mPa·s), methylenechloride, methylparaben, methylparaben sodium, microcrystallinecellulose, microcrystalline wax, mineral oil, mint, mint cream flavor,mint menthol, modified corn starch, monosodium citrate, natural andartificial orange flavor, natural flavor, natural mint flavor, naturalpeppermint flavor, natural resin, nonoxynol-100, oleic acid, olive oil,opacode black, orange cream flavor, orange juice, orange oil,orange-pineapple flavor, other ingredients known to those skilled in theart, palm kernel oil, paraffin, partially hydrogenated soybean and palmoils, peanut oil, peppermint, peppermint flavor, peppermint oil,pharmaceutical glaze, phenylalanine, phosphoric acid, piperazine,polacrilin potassium, polacrilin sodium, poloxamer, poloxamer 188,poloxamer 407, polyacrylate dispersion 30%, polycarbophil, polydextrose,polyethylene glycol, polyethylene glycol 1450, polyethylene glycol 300,polyethylene glycol 3000, polyethylene glycol 3350, polyethylene glycol400, polyethylene glycol 4000, polyethylene glycol 600 polyethyleneglycol 6000, polyethylene glycol 800, polyethylene glycol 8000,polygalacturonic acid, polyplasdone xl, polysorbate, polysorbate 20,polysorbate 80, polyvinyl acetate, polyvinyl alcohol,polyvinylpyrrolidone, potassium, potassium bicarbonate, potassiumbitartrate, potassium carbonate, potassium carbonate anhydrous,potassium chloride, potassium gluconate, potassium hydroxide, potassiumsorbate, potato starch, povidone, povidone k12, povidone k25, povidonek29/32, povidone k30, povidone k90, precipitated calcium carbonate,pregelatinized corn starch, pregelatinized starch, propyl gallate,propylene glycol, propylene glycol alginate, propylparaben,propylparaben sodium, raspberry, raw sugar, riboflavin, rice starch,saccharin, saccharin sodium, sd-45 alcohol, sda-3a alcohol, sesame oil,shellac, silicified microcrystalline cellulose, silicon dioxide, silicondioxide colloidal, silicone, simethicone, simethicone emulsion, sodium,sodium alginate, sodium ascorbate, sodium benzoate, sodium bicarbonate,sodium carbonate, sodium carbonate monohydrate, sodium caseinate, sodiumchloride, sodium citrate, sodium citrate dehydrate, sodium glycolate,sodium hydroxide, sodium laureth sulfate, sodium lauryl sulfate, sodiumlauryl sulphate, sodium metabisulfite, sodium monolaurate, sodiumphosphate, sodium phosphate dibasic, sodium propionate, sodium starchglycolate, sodium starch glycolate type A potato, sodium stearate,sodium stearyl fumarate, sodium thioglycolate, sodium tripolyphosphate,sorbic acid, sorbitan, sorbitan monolaurate, sorbitan monooleate,sorbitol, sorbitol special, soya lecithin, soybean oil, spearmint,starch, stearic acid, stearyl alcohol, strawberry, strawberry guaranaflavor, strong ammonia solution, succinic acid, sucralose, sucrose,sucrose stearate, sugar 6× powder, sugar spheres, sunflower oil,synthetic ferric oxide, synthetic ferric oxide black, synthetic ferricoxide red, synthetic ferric oxide yellow, synthetic ferric oxides,tapioca starch, tartaric acid, tartrazine, taurine, TIMERx-N, titaniumdioxide, titanium oxide, tragacanth, triacetin, tribehenin, tricalciumphosphate, triethyl citrate, trimyristin, trisodium citrate anhydrous,trisodium citrate dehydrate, tromethamine, tropical blend flavor,vanilla, vanilla flavor, vanillin, vitamin e, water, wax, wheat starch,white wax, xanthan gum, xylitol, yellow wax, zinc gluconate, zincstearate.

Buffering systems affect the physical stability and appearance of drugformulations. A variety of buffering systems are known in the art andinclude various forms of acetates (especially acetic acid and sodiumacetate), citrates (especially citric acid and sodium citrate), andphosphates (especially sodium phosphate and disodium phosphate). Duringthe development process, addition of simethicone to the formulationresulted in an unacceptable marbled and thin suspension at higher APIloading (100 mg/5 ml). Subsequent addition of a proprietarycitrate:phosphate buffer system was shown to improve the appearance andphysical stability of the inventive formulations across all product APIstrengths.

Alcohol, benzoates, parabens, phenols, quaternary ammonium compounds(i.e., quats), sorbic acid, salts and other substances generally knownto one of skill in the art have all been employed as preservative agentsfor suspension formulations. A proprietary blend of methylhydroxybenzoate and propyl hydroxybenzoate was selected as apreservative system as it demonstrated synergistic antimicrobialactivity in the pH range of the inventive composition of matter.

All formulations showing product stability (e.g., 12.5 mg/5 ml, 25 mg/5ml and 100 mg/5 ml) were scaled up as part of the process validation(PV) exercise. PV batches were manufactured using the final productionequipment and facility to cGMP and compared to a reference product(SEROQUEL™ 25 mg Tablets) using dissolution (paddles 50 RPM) at three pHlevels (i.e., 1.2, 4.5 and 6.8). Dissolution at all pH levels was equalto or greater than approximately 75% in 15 minutes, thus demonstratingbioequivalence. The outcome of bioequivalence studies revealed that the25 mg/5 ml suspension was bioequivalent to SEROQUEL™ 25 mg tablets andthe 100 mg/5 ml suspension was bioequivalent to SEROQUEL™ 100 mg tablet.

FIG. 16a describes the particle size and viscosity data for 12.5 mg/5ml, 25 mg/5 ml and 100 mg/5 ml 10 L validation batches at 5° C. FIG. 16bdescribes particle sizes for additional production scale batches. FIG.16c describes viscosity data for additional production scale batches.

FIG. 17 describes the 90% confidence intervals for quetiapine meantest/reference ratios. The 90% confidence intervals of thetest/reference ratio for AUC and C_(max) values for quetiapine liewithin the acceptable limits of 80.00% to 125.00%, in line with the“Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98Rev 1/Corr**). Thus, the data support the claim that the disclosed 20mg/ml oral liquid quetiapine suspension product is bioequivalent to thereference product SEROQUEL™ 100 mg film-coated tablets (Astra Zeneca UKLimited).

It is envisaged that the product would be supplied in an Amber glass(Type III) container with a childproof closure.

The present formulation is a novel and nonobvious improvement overpreviously described oral quetiapine formulations (both extemporaneouslyprepared aqueous and commercially approved solid formulations) becausethe inventive drug formulation allows for uniform and consistentdelivery of drug substance to a patient in need thereof throughout theentire extended shelf life of the product.

Organoleptic ingredients improve the taste and appearance and do notnegatively affect the suspension stability. The organoleptic agents inthe following examples include coloring and flavoring agents, sweetenersand masking agents.

The suspension has antimicrobial activity as disclosed in FIG. 1. It isconceivable that other compatible antimicrobial excipients may also beused.

Mutual compatibility of the components means that the components do notseparate in preparation and storage for up to the equivalent of twoyears at room temperature. Storage stability means that the materials donot lose their desirable properties during storage for the same period.

“Active agent” generally means a compound, macromolecule, element,substance, or mixture that when administered to a patient, alone or incombination with another compound, macromolecule, element, substance, ormixture, confers, directly or indirectly, a physiological effect on thepatient. When the active agent is a compound, then salts, solvates(including hydrates), esters, and prodrugs of the compound arecontemplated herein. Furthermore, crystalline forms, non-crystallineforms, polymorphs and any pseudo-polymorphs of the compound are alsocontemplated herein.

“Bioavailability” generally means the extent or rate at which an activeagent is absorbed into a living system or is made available at the siteof physiological activity. Bioavailability can be characterized by oneor more pharmacokinetic parameters. “Pharmacokinetic parameters”describe the in vivo characteristics of an active agent (or surrogatemarker for the active agent) over time, such as plasma concentration(C), C_(max), C_(n), C₂₄, T_(max), and AUC. “C_(max)” is the measuredconcentration of the active agent in the plasma at the point of maximumconcentration. “C_(n)” is the measured concentration of an active agentin the plasma at about n hours after administration. “C₂₄” is themeasured concentration of an active agent in the plasma at about 24hours after administration. The term “T_(max)” refers to the time atwhich the measured concentration of an active agent in the plasma is thehighest after administration of the active agent. “AUC” is the areaunder the curve of a graph of the measured concentration of an activeagent (typically plasma concentration) vs. time, measured from one timepoint to another time point. For example AUC_(0-t) is the area under thecurve of plasma concentration versus time from time 0 to time t.AUC_(0-INF) is the calculated area under the curve of plasmaconcentration versus time from time 0 to time infinity. FIG. 18describes the pharmacokinetic parameters of the inventive oralquetiapine fumarate liquid suspension product.

In some embodiments, the oral liquid suspension composition isbioequivalent to a reference drug. “Reference drug” means an activepharmaceutical ingredient product as described in the U.S. Federal Foodand Drug Administration's (FDA) Orange Book, Approved Drug Products withTherapeutic

Equivalence Evaluations or the European Medicines Agency (EMEA) document“Note for Guidance on the Investigation of Bioavailability andBioequivalence. In a preferred embodiment, the reference drug isSEROQUEL™ approved by the U.S. FDA under NDA020639.

In one embodiment, the reference drug is a Seroquel®, i.e., a quetiapinefumarate product was initially described in U.S. Federal Food and DrugAdministration's New Drug Application No. 20639 and approved for use onSep. 26, 1997 and which is listed in the U.S. Federal Food and DrugAdministration's Orange Book, as the RLD or “reference listed drug” forgeneric equivalents thereof.

Under U.S. FDA guidelines, two products (e.g. an inventive compositionand brand drug) or methods (e.g., dosing under non-fasted versus fastedconditions) are bioequivalent if the 90% Confidence Interval (CI) limitsfor a ratio of the geometric mean of logarithmic transformedAUC_(0-INF), AUC_(0-t) and C_(max) for the two products or two methodsare about 0.80 to about 1.25.

To show bioequivalence between two compounds or administrationconditions pursuant to Europe's EMEA guidelines, the 90% CI limits for aratio of the geometric mean of logarithmic transformed AUC_(0-INF),AUC_(0-t) for the two products or methods are about 0.80 to about 1.25.The 90% CI limits for a ratio of the geometric mean of logarithmictransformed C_(max) for the two products or methods can have a wideracceptance range when justified by safety and efficacy considerations.

“Bioequivalence” means the absence of a significant difference in therate and extent to which the active agent or surrogate marker for theactive agent in pharmaceutical equivalents or pharmaceuticalalternatives becomes available at the site of action when administeredin an appropriately designed study.

The term “pharmaceutically acceptable” generally means suitable for usein contact with the tissues of humans and animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended usewithin the scope of sound medical judgment.

By “pharmaceutically effective amount”, it is generally meant the amountof an active agent that, when administered to a patient for treating adisease, is sufficient to effect such treatment for the disease. Apharmaceutically effective amount will vary depending on the activeagent, the disease and its severity, and the age, weight, and otherconditions of the patient to be treated.

“Salts” include derivatives of an active agent, wherein the active agentis modified by making acid or base additions thereof.

“Solvate” means a complex formed by solvation (the combination ofsolvent molecules with molecules or ions of the active agent of thepresent invention), or an aggregate that consists of a solute ion ormolecule (the active agent of the present invention) with one or moresolvent molecules.

“Shelf Stability” generally refers to the longest length of time in thelabeling or approval documentation accompanying a commercially approveddrug formulation. In an embodiment, the labeling or approvaldocumentation originates from the European Medicines Agency. In anotherembodiment, the labeling or approval documentation originates from theU.S. Food and Drug Agency (FDA).

“D(0.9) value” refers to the threshold at which 90% of the particles ina sample are expected to be smaller as measured by particle sizediameter. Unless noted otherwise, all D(0.9) values are in μm.

The foregoing describes the invention, including preferred formsthereof, alterations or modifications as would be understood to a personskilled in this particular art are intended to be included within thescope of the invention as claimed. In describing embodiments of thepresent invention, specific terminology is employed for the sake ofclarity. However, the invention is not intended to be limited to thespecific terminology so selected. It is to be understood that eachspecific element includes all technical equivalents, which operate in asimilar manner to accomplish a similar purpose. The describedembodiments of the invention may be modified or varied, and elementsadded or omitted, without departing from the invention, as appreciatedby those skilled in the art in light of the disclosed teachings. Eachreference cited herein is incorporated by reference as if each wereindividually incorporated by reference.

We claim:
 1. A pharmaceutical composition comprising a pharmaceuticallyeffective amount of quetiapine fumarate particles dispersed insuspension, wherein the composition is suitable for oral delivery,comprises mutually compatible components, has a pH between about 5.0 and6.0, is palatable, and is storage stable.
 2. The composition of claim 1,wherein the composition viscosity is approximately 700-2000 cP.
 3. Thecomposition of claim 2, wherein the quetiapine fumarate concentration is12.5 mg/5 ml.
 4. The composition of claim 2, wherein the quetiapinefumarate concentration is 25 mg/5 ml.
 5. The composition of claim 2,wherein the quetiapine fumarate concentration is 100 mg/5 ml.
 6. Thecomposition of claim 2, wherein the quetiapine fumarate concentration is200 mg/5 ml.
 7. The composition of claim 5 that is bioequivalent tocommercially approved solid dosage formulations of quetiapine fumarate.8. The composition of claim 1 that is at least 24-month storage stableat 2 to 8 degrees centigrade.
 9. The composition of claim 1, whereinapproximately ninety percent of the quetiapine fumarate startingmaterial has a maximum particle diameter between 20 m and 70 m.
 10. Thecomposition of claim 1, wherein the D(0.9) value of the 12.5 mg/5 mlfinal product is approximately 60 to 120 μm and viscosity approximately1050 to 1800 cP.
 11. The composition of claim 1, wherein the D(0.9)value of the 25 mg/5 ml final product is approximately 60 to 120 μm andviscosity approximately 790 to 1200 cP.
 12. The composition of claim 1,wherein the D(0.9) value of the 100 mg/5 ml final product isapproximately 60 to 120 μm and viscosity approximately 1180 to 1400 cP.13. The composition of claim 1, wherein about 70% or more of thequetiapine fumarate is fully dissolved in 45 minutes.
 14. Thecomposition of claim 1, wherein the quetiapine fumarate is substantiallycomprised of the Form 1 polymorph.
 15. A process for the manufacture ofa pharmaceutical composition comprising a pharmaceutically effectiveamount of quetiapine fumarate particles dispersed in suspensioncomprising: adding purified water to a main vessel, adding citric acidmonohydrate to the main vessel and mixing until dissolved using ahigh-shear mixer, adding disodium hydrogen phosphate dihydrate to themain vessel and mixing until dissolved using a high-shear mixer, addingsucralose to the main vessel and mixing until dissolved using ahigh-shear mixer, adding the simethicone emulsion to the main vessel andmixing until dispersed using a high-shear mixer, adding quetiapinefumarate to the main vessel and mixing using a high-shear mixer until ahomogeneous suspension is produced, to a separate stage vessel addingpropylene glycol, to the separate stage vessel adding methylhydroxybenzoate, to the separate stage vessel adding propylhydroxybenzoate and mixing using a high-shear mixer until dissolved, tothe preservative solution in the separate stage vessel adding xanthangum and mixing until homogenous using a propeller mixer, adding thepreservative solution/xanthan gum slurry in the separate stage vessel tothe main vessel and mixing using a high-shear mixer until a uniformlythickened suspension is produced, adding the lemon flavour to the mainvessel and mixing with a high-shear mixer until dispersed, checking thepH of the solution (target pH is 5.50), wherein if the pH is outside therange of 5.2-5.8 adjusting the pH until it within this range by usingeither 10% w/v citric acid monohydrate solution to lower pH or a 10% w/vdisodium hydrogen phosphate dihydrate solution to increase the pH,adding purified water to final volume and mixing until dispersed using ahigh-shear mixer, filling 152±2 ml of finished product into 180 ml amberglass bottles and closing with child resistant closures.
 16. A methodfor treating a patient in need of quetiapine fumarate, comprising thestep of orally administering a therapeutically effective amount of thepharmaceutical composition of claim
 1. 17. The method of claim 16,wherein the patient in need of quetiapine fumarate is suffering from amedical condition or symptom selected from the group consisting of:Schizophrenia and other Psychotic Disorders including but not limited toPsychotic Disorder, Schizophreniform Disorder, Schizoaffective Disorder,Delusional Disorder, Brief Psychotic Disorder, Shared PsychoticDisorder, and Psychotic Disorder Due to a General Medical Condition;Dementia and other Cognitive Disorders; Anxiety Disorders including butnot limited to Panic Disorder Without Agoraphobia, Panic Disorder WithAgoraphobia, Agoraphobia Without History of Panic Disorder, SpecificPhobia, Social Phobia, Obsessive-Compulsive Disorder, PosttraumaticStress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder andGeneralized Anxiety Disorder Due to a General Medical Condition; MoodDisorders including but not limited to a) Depressive Disorders,including but not limited to Major Depressive Disorder and DysthymicDisorder and b) Bipolar Depression and/or Bipolar mania including butnot limited to Bipolar I Disorder, including but not limited to thosewith manic, depressive or mixed episodes, and Bipolar n Disorder, c)Cyclothymic Disorder, d) Mood Disorder Due to a General MedicalCondition; Sleep Disorders; Disorders Usually First Diagnosed inInfancy, Childhood, or Adolescence including but not limited to MentalRetardation, Learning Disorders, Motor Skills Disorder, CommunicationDisorders, Pervasive Developmental Disorders, Attention-Deficit andDisruptive Behavior Disorders, Feeding and Eating Disorders of Infancyor Early Childhood, Tic Disorders, and Elimination Disorders;Substance-Related Disorders including but not limited to SubstanceDependence, Substance Abuse, Substance Intoxication, SubstanceWithdrawal, Alcohol-Related Disorders, Amphetamine (orAmphetamine-Like)-Related Disorders, Caffeine-Related Disorders,Cannabis-Related Disorders, Cocaine-Related Disorders,Hallucinogen-Related Disorders, Inhalant-Related Disorders,Nicotine-Related Disorders, Opioid-Related Disorders, Phencyclidine (orPhencyclidine-Like)-Related Disorders, and Sedative-, Hypnotic- orAnxiolytic-Related Disorders; Attention-Deficit and Disruptive BehaviorDisorders; Eating Disorders; Personality Disorders including but notlimited to Obsessive-Compulsive i Personality Disorder; andImpulse-Control Disorders, comprising administering to a mammal atherapeutically effective amount of a formulation of the invention. 18.The method of claim 16 further comprising co-administering atherapeutically effective amount of at least one other neuropsychiatricactive agent to a patient in need thereof.
 19. The method of claim 16,wherein the patient suffering from bipolar disorder is being treatedwith quetiapine fumarate as an adjunct to lithium or divalproex.